This invention relates to a process for obtaining 17xcex2-(N-tert-butylcarbamoyl) -3-one-4-aza-steroids, optionally unsaturated between carbons 1-2 or 5-6, useful as inhibitors of 5xcex1-reductase or synthetic intermediates thereof.
4-aza-steroids are known that are useful as inhibitors of the enzyme 5xcex1-reductase, an enzyme that converts testosterone into the more potent androgen, 5xcex1-dihydro-testosterone, which is the main mediator of the androgenic activity in some organs. The inhibitors of testosterone-5xcex1-reductase may prevent or reduce the symptoms of hyperandrogenic stimulation.
U.S. Pat. No. 4,760,071 describes some 17xcex2-(N-alkyl-carbamoyl)-4-aza-5xcex1-androst-1-en-3-ones useful as inhibitors of 5xcex1-reductase. A representative example of said compounds is finasteride [17xcex2-(N-tert-butyl-carbamoyl)-4-aza-5xcex1-androst-1-en-3-one], an active substance with multiple therapeutic applications, for example, in the treatment of benign prostatic hyperplasia and alopecia.
Known processes for obtaining 17xcex2- (N-tert-butylcarbamoyl)-3-one-4-aza-steroids comprise the formation of a N-tert-butylcarbamoyl group.
The general processes for obtaining amides consist of reacting a derivative of carboxylic acid with the corresponding amine. The derivative of carboxylic acid may be an acid halide, an ester, a derivative of carbonyl or thionyl imidazole, a derivative of dicyclohexylcarbodiimide, etc.
When the derivative of carboxylic acid is an ester, its reaction with the amine to form the amide occurs satisfactorily when the ester and the amine have certain characteristics, such as high reactivity and absence of steric hindrance. When the structure of the ester and that of the amine are complex, the reactivity between both compounds reduces and the level of transformation may be practically zero. This occurs, for example, in the formation of 17xcex2-(N-tert-butylcarbamoyl)-3-one-4-aza-steroids starting from 17xcex2-(alkoxycarbonyl)-3-one-4-aza-steroids and tert-butyl-amine. In this case, said esters are not very reactive and the amine [tert-butylamine] presents a clear steric hindrance.
The solutions proposed in the state of the art for solving the problem of low reactivity between said esters and tert-butylamine may be sorted out in 3 groups:
a) those in which the amine is allowed to react with another derivative of carboxylic acid that confers on it greater reactivity, such as an acid halide; a representative example of this group is mentioned in U.S. Pat. No. 5,670,643, where the conversion of 17xcex2-carboxy-4-aza-5xcex1-androst-1-en-3-one into the corresponding acid chloride is described [see Example 1 of said U.S. Pat. No. 5,670,643]. This alternative, applied to an ester as a starting material, would imply the conversion of the ester into the acid and, subsequently, the conversion of the acid into the corresponding derivative, which would suppose the need of some additional synthetic steps that draw out the process and reduce the yield;
b) those in which the amine is activated by means of the formation of the corresponding derivative of magnesium-alkylamine by reacting the amine with a Grignard compound [see Examples 1 and 2 of the European patent application EP-A-0 655 458]. This alternative has the drawback that side reactions are produced by the presence of the Grignard compound in the reaction medium which may react with the ester group itself; and
c) those which combine the conversion of the ester into a more reactive derivative and the activation of the amine, for example, the conversion of 17xcex2-carboxy-4-aza-5xcex1-androst-1-en-3-one into the corresponding derivative of imidazole and the conversion of the amine into the corresponding derivative of alkylaminomagnesium [see Example 5 of the patent application EP-A-0 367 502]. This alternative has the drawbacks of the alternatives a) and b).
The process of the present invention overcomes the whole or part of the drawbacks present in the processes of the state of the art.